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Microcephaly in Brazil: confidence builds in Zika connection

2016; Elsevier BV; Volume: 16; Issue: 5 Linguagem: Inglês

10.1016/s1473-3099(16)30015-9

1474-4457

Marcia Triunfol,

Mosquito-borne diseases and control

Brazil has remained at the epicentre of Zika virus research and its potential connection to developmental abnormalities. Marcia Triunfol reports.The number of cases of Zika virus infection continues to climb in Brazil despite efforts by the Brazilian government to prevent the mosquito Aedes aegypti from breeding. In Brazil, Zika virus infection has manifested in ways that vary from a mild cold-like episode, to severe joint pain and Guillain-Barré syndrome—a rare autoimmune disease that can cause muscle weakness, numbness, and tingling, and that can be fatal in some cases.However, health authorities everywhere agree that the most chilling aspect of the Zika outbreak in Brazil is the potential association between the virus and the increasing incidence of congenital microcephaly and other abnormalities of the CNS in fetuses and newborn babies of mothers who were infected by the virus during pregnancy.According to the latest epidemiological bulletin issued by the Brazilian Ministry of Health, as of April 2, 2016, there were 6906 reported cases of microcephaly, other congenital abnormalities of the CNS, or both. Of these, 4046 are still under investigation. The occurrence of microcephaly and other CNS abnormalities has been confirmed in 1046 cases so far, which represents roughly 37% of cases already investigated. The state of Pernambuco, in the northeast region of Brazil, remains the leader in notified cases of microcephaly, with 1846 cases reported since the first epidemiological bulletin was issued by the Brazilian health authorities in the second half of November 2015. It is not clear what these numbers really mean.A study posted to the WHO Zika Open site on February 2016 clearly shows that the situation in the state of Pernambuco is not as alarming as initially thought. A task force set up to investigate medical reports and hospital data of 16 208 neonates born in the state between Jan 1, 2012, and Dec 31, 2015, in 21 different public health centres found that, depending on the criteria adopted to define microcephaly (head circumference of 32 cm, the Fenton curve, or proportionality criteria), between 4% and 8% of all babies born during the period had microcephaly. According to official data provided by the Ministry of Health, from 2010 to 2015 the incidence of microcephaly in the entire country was 180 cases per year. These contrasting findings indicate that historical series of data need to be recreated in order to better understand the dimension of Zika-related congenital microcephaly in Brazil.In a recent preliminary study, a group of researchers in Brazil teamed up with researchers from the Biomedical Research Institute of Southern California to follow 88 pregnant women from September 2015 to February 2016 at the Fernandes Figueira Institute in Rio de Janeiro, a reference centre for children with congenital malformations and rare genetic diseases. Women included in the study presented a skin rash that appeared at any point in their pregnancy (with a range of 5–38 weeks of gestation), and had specimens (serum, urine, blood) collected within 5 days of the appearance of the skin rash, for PCR analysis. 88% of the women included in the study had dengue IgG antibodies. Of the 88 women, 72 had Zika infection confirmed by PCR but only 42 had prenatal ultrasonography examinations during pregnancy. Of the 42 women followed up by the study group, a total of 12 (29%) had fetuses presenting abnormal Doppler ultrasonography results, with or without microcephaly. For Cesar Victora, an epidemiologist at the Federal University of Pelotas and an author of a Comment in The Lancet on how to interpret reported numbers of microcephaly in Brazil, the study findings are alarming. “What shocked me the most was to learn that of all pregnant women followed prospectively, one third had either fetuses or neonates presenting some type of neurological abnormality”, says Victora.For Fernando Kok, a physician specialising in neuropaediatrics and a professor at the University of São Paulo, the outcome of each baby in the study group still needs to be confirmed, as only eight of the 42 women followed up have delivered their babies. Kok argues that Doppler ultrasonography findings do not always match the changes observed in the neonate. Indeed, at least one infant in the study presented normal growth measures at birth despite ultrasonography done at 40 weeks of pregnancy suggesting otherwise. Kok also believes that babies who had normal ultrasound exams while fetuses may present abnormalities later, and concludes by saying “these numbers will still fluctuate”.Both researchers were surprised to learn that infection with Zika virus can cause congenital abnormalities irrespective of pregnancy stage at infection. But Patricia Brasil, a researcher at the Evandro Chagas Institute at the Oswaldo Cruz Foundation in Rio de Janeiro, observes that the abnormalities presented in women infected in the last trimester were more often in the placenta (placentitis). “In some cases, a medical intervention may prevent the additional complications”, she said.In Brasil's study, five fetuses of 12 showed in-utero growth restriction (irrespective of the presence of microcephaly), six had ventricular calcifications or other lesions of the CNS, and four had abnormal cerebral or umbilical artery flow or fluid volume. Two fetuses presented oligohydramnios and anhydramnios and two were dead after 30 weeks of gestation. Some of the abnormalities observed occurred simultaneously in the same fetus.It could be argued that the fact that pregnant women included in the study were selected by the presence of a skin rash may have exaggerated the risk of congenital microcephaly or other CNS abnormalities, as the skin rash may be a function of high viral load that is potentially translated into severe symptoms in fetuses. However, Brasil advises that the study has limitations that do not allow calculation of risk. To calculate risk, she explains, “you would need a control group with women who do not present the skin rash, besides that a much larger sample would need to be studied”. In fact, the goal of the study was limited to finding evidence of a link between pregnant women infected with Zika virus and the presence of microcephaly or any other abnormality, as many in the scientific community have been sceptical of such an association.But not all in the community are sceptical. For Lavinia Schüler-Faccini, president of the Brazilian Society of Medical Genetics and a professor at the Federal University of Rio Grande do Sul, not only is the connection clear but Zika-related congenital abnormalities also go beyond microcephaly and present as a unique phenotype. “What we have been seeing in these babies is a new phenotype characterised by a type of microcephaly that is different than the ones seen in other infections. For instance, the heads of these babies are flattened and the posterior side of the skull seems to have dropped due to a lack of support. Also, these babies have tremors, irritability, seizures, and a remarkable lack of proportions between the skull and the face.” Schüler-Faccini also adds that the type and level of damage observed in these babies is similar to that observed in animals such as sheep, cattle, and swine infected by Japanese encephalitis virus and the Cache Valley virus. The pattern observed by Schüler-Faccini includes microcephaly, presence of cerebrospinal fluid occupying the empty undeveloped areas of the brain, changes in the retina, and difficulties in moving the joints, among others. Similar to what has been observed by the group of Patricia Brasil, Lavinia Schüler-Faccini and her group indicate that infection in the early stages of pregnancy is more severe than infection occurring in the last trimester.One important question still needs to be answered, Cesar Victora reminds us. If a woman is infected with Zika virus during pregnancy, what are her chances of having a baby with some type of neurological abnormality? For this risk to be calculated, new studies that evaluate a larger group of women will be necessary as well as development of new diagnostic tests. PCR, the only diagnostic tool currently available to confirm Zika, can only detect active infection.Luis Carlos de Souza Ferreira, a researcher and the vice-director of the Biomedical Sciences Institute of University of São Paulo, has taken the first steps in developing a serological test for the diagnosis of Zika virus infection. The test, which uses a modified viral NS1 structural protein as the antigen, has shown a high level of specificity when tested in 300 people infected with Zika virus. Now the group is providing other research groups in the country with the test for widescale evaluation. Besides helping calculate the risk of having a baby with Zika-related congenital abnormality, Souza Ferreira believes that the new test will also allow the enumeration of Zika virus infections since the beginning of the outbreak in Brazil.For Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, the findings described in the study of the 88 pregnant women represent the strongest evidence yet of a connection between the virus and neurological abnormalities in fetuses and neonates. But why this association is being seen mostly in Brazil and not in other countries with Zika outbreaks, is just one more question looking for answers. Brazil has remained at the epicentre of Zika virus research and its potential connection to developmental abnormalities. Marcia Triunfol reports. The number of cases of Zika virus infection continues to climb in Brazil despite efforts by the Brazilian government to prevent the mosquito Aedes aegypti from breeding. In Brazil, Zika virus infection has manifested in ways that vary from a mild cold-like episode, to severe joint pain and Guillain-Barré syndrome—a rare autoimmune disease that can cause muscle weakness, numbness, and tingling, and that can be fatal in some cases. However, health authorities everywhere agree that the most chilling aspect of the Zika outbreak in Brazil is the potential association between the virus and the increasing incidence of congenital microcephaly and other abnormalities of the CNS in fetuses and newborn babies of mothers who were infected by the virus during pregnancy. According to the latest epidemiological bulletin issued by the Brazilian Ministry of Health, as of April 2, 2016, there were 6906 reported cases of microcephaly, other congenital abnormalities of the CNS, or both. Of these, 4046 are still under investigation. The occurrence of microcephaly and other CNS abnormalities has been confirmed in 1046 cases so far, which represents roughly 37% of cases already investigated. The state of Pernambuco, in the northeast region of Brazil, remains the leader in notified cases of microcephaly, with 1846 cases reported since the first epidemiological bulletin was issued by the Brazilian health authorities in the second half of November 2015. It is not clear what these numbers really mean. A study posted to the WHO Zika Open site on February 2016 clearly shows that the situation in the state of Pernambuco is not as alarming as initially thought. A task force set up to investigate medical reports and hospital data of 16 208 neonates born in the state between Jan 1, 2012, and Dec 31, 2015, in 21 different public health centres found that, depending on the criteria adopted to define microcephaly (head circumference of 32 cm, the Fenton curve, or proportionality criteria), between 4% and 8% of all babies born during the period had microcephaly. According to official data provided by the Ministry of Health, from 2010 to 2015 the incidence of microcephaly in the entire country was 180 cases per year. These contrasting findings indicate that historical series of data need to be recreated in order to better understand the dimension of Zika-related congenital microcephaly in Brazil. In a recent preliminary study, a group of researchers in Brazil teamed up with researchers from the Biomedical Research Institute of Southern California to follow 88 pregnant women from September 2015 to February 2016 at the Fernandes Figueira Institute in Rio de Janeiro, a reference centre for children with congenital malformations and rare genetic diseases. Women included in the study presented a skin rash that appeared at any point in their pregnancy (with a range of 5–38 weeks of gestation), and had specimens (serum, urine, blood) collected within 5 days of the appearance of the skin rash, for PCR analysis. 88% of the women included in the study had dengue IgG antibodies. Of the 88 women, 72 had Zika infection confirmed by PCR but only 42 had prenatal ultrasonography examinations during pregnancy. Of the 42 women followed up by the study group, a total of 12 (29%) had fetuses presenting abnormal Doppler ultrasonography results, with or without microcephaly. For Cesar Victora, an epidemiologist at the Federal University of Pelotas and an author of a Comment in The Lancet on how to interpret reported numbers of microcephaly in Brazil, the study findings are alarming. “What shocked me the most was to learn that of all pregnant women followed prospectively, one third had either fetuses or neonates presenting some type of neurological abnormality”, says Victora. For Fernando Kok, a physician specialising in neuropaediatrics and a professor at the University of São Paulo, the outcome of each baby in the study group still needs to be confirmed, as only eight of the 42 women followed up have delivered their babies. Kok argues that Doppler ultrasonography findings do not always match the changes observed in the neonate. Indeed, at least one infant in the study presented normal growth measures at birth despite ultrasonography done at 40 weeks of pregnancy suggesting otherwise. Kok also believes that babies who had normal ultrasound exams while fetuses may present abnormalities later, and concludes by saying “these numbers will still fluctuate”. Both researchers were surprised to learn that infection with Zika virus can cause congenital abnormalities irrespective of pregnancy stage at infection. But Patricia Brasil, a researcher at the Evandro Chagas Institute at the Oswaldo Cruz Foundation in Rio de Janeiro, observes that the abnormalities presented in women infected in the last trimester were more often in the placenta (placentitis). “In some cases, a medical intervention may prevent the additional complications”, she said. In Brasil's study, five fetuses of 12 showed in-utero growth restriction (irrespective of the presence of microcephaly), six had ventricular calcifications or other lesions of the CNS, and four had abnormal cerebral or umbilical artery flow or fluid volume. Two fetuses presented oligohydramnios and anhydramnios and two were dead after 30 weeks of gestation. Some of the abnormalities observed occurred simultaneously in the same fetus. It could be argued that the fact that pregnant women included in the study were selected by the presence of a skin rash may have exaggerated the risk of congenital microcephaly or other CNS abnormalities, as the skin rash may be a function of high viral load that is potentially translated into severe symptoms in fetuses. However, Brasil advises that the study has limitations that do not allow calculation of risk. To calculate risk, she explains, “you would need a control group with women who do not present the skin rash, besides that a much larger sample would need to be studied”. In fact, the goal of the study was limited to finding evidence of a link between pregnant women infected with Zika virus and the presence of microcephaly or any other abnormality, as many in the scientific community have been sceptical of such an association. But not all in the community are sceptical. For Lavinia Schüler-Faccini, president of the Brazilian Society of Medical Genetics and a professor at the Federal University of Rio Grande do Sul, not only is the connection clear but Zika-related congenital abnormalities also go beyond microcephaly and present as a unique phenotype. “What we have been seeing in these babies is a new phenotype characterised by a type of microcephaly that is different than the ones seen in other infections. For instance, the heads of these babies are flattened and the posterior side of the skull seems to have dropped due to a lack of support. Also, these babies have tremors, irritability, seizures, and a remarkable lack of proportions between the skull and the face.” Schüler-Faccini also adds that the type and level of damage observed in these babies is similar to that observed in animals such as sheep, cattle, and swine infected by Japanese encephalitis virus and the Cache Valley virus. The pattern observed by Schüler-Faccini includes microcephaly, presence of cerebrospinal fluid occupying the empty undeveloped areas of the brain, changes in the retina, and difficulties in moving the joints, among others. Similar to what has been observed by the group of Patricia Brasil, Lavinia Schüler-Faccini and her group indicate that infection in the early stages of pregnancy is more severe than infection occurring in the last trimester. One important question still needs to be answered, Cesar Victora reminds us. If a woman is infected with Zika virus during pregnancy, what are her chances of having a baby with some type of neurological abnormality? For this risk to be calculated, new studies that evaluate a larger group of women will be necessary as well as development of new diagnostic tests. PCR, the only diagnostic tool currently available to confirm Zika, can only detect active infection. Luis Carlos de Souza Ferreira, a researcher and the vice-director of the Biomedical Sciences Institute of University of São Paulo, has taken the first steps in developing a serological test for the diagnosis of Zika virus infection. The test, which uses a modified viral NS1 structural protein as the antigen, has shown a high level of specificity when tested in 300 people infected with Zika virus. Now the group is providing other research groups in the country with the test for widescale evaluation. Besides helping calculate the risk of having a baby with Zika-related congenital abnormality, Souza Ferreira believes that the new test will also allow the enumeration of Zika virus infections since the beginning of the outbreak in Brazil. For Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, the findings described in the study of the 88 pregnant women represent the strongest evidence yet of a connection between the virus and neurological abnormalities in fetuses and neonates. But why this association is being seen mostly in Brazil and not in other countries with Zika outbreaks, is just one more question looking for answers.